Atherosclerosis and coronary heart disease in man are often associated with elevation of the plasma lipids. Evidence indicates that some genetic forms of hyperlipidemia result from an abnormality in the regulation of cholesterol synthesis in liver. In animals exogenous cholesterol profoundly inhibits hepatic cholesterol synthesis by reducing the activity of the microsomal enzyme Beta-hydroxy-Beta-methylglutaryl coenzyme A reductase (HMG CoA reductase) which catalyzes the first reaction specific to cholesterol biosynthesis. We have succeeded in solubilizing HMG CoA reductase from rat liver microsomes and have achieved the first successful purification of the enzyme in high yield. We have described several unique properties of the enzyme which permit its stabilization and facilitate further study. In addition, we have been able to demonstrate HMG CoA reductase activity in human liver for the first time and have characterized the enzyme in cell cultures of human fibroblasts. Moreover, we have obtained evidence for the regulation of human HMG CoA reductase by serum lipoproteins in tissue culture. We now propose: 1) to purify HMG CoA reductase to homogeneity from rat and human liver and to study the molecular basis for the regulation of its activity; 2) to delineate the mechanism for the regulation of this activity in human tissues in culture; and 3) to study the enzyme and its regulation in patients with hypercholesterolemia in order to elucidate the defect which may produce familial hypercholesterolemia.